Proteomic alterations of distinct mitochondrial subpopulations in the type 1 diabetic heart: contribution of protein import dysfunction
Proteomic alterations of distinct mitochondrial subpopulations in the type 1 diabetic heart: contribution of protein import dysfunction
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DOI：
10.1152/ajpregu.00423.2010
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发表时间：
2011-02-01
影响因子：
2.8
通讯作者：
Hollander, John M.
中科院分区：
文献类型：
--
作者：
Baseler, Walter A.;Dabkowski, Erinne R.;Hollander, John M.
巴塞尔瓦，达布科夫斯基，威廉姆森CL，克罗斯顿TL，塔帕D，鲍威尔MJ，Razunguzwa TT，Hollander JM。1型糖尿病心脏不同线粒体亚群的蛋白质组学改变：蛋白质导入功能障碍的贡献。Am J Physiol Regul Integr Comp Physiol 300：R186-R200,2011。2010年11月3日首次出版；DOI：10.1152/ajpregu.00423.2010。-糖尿病心肌病与1型糖尿病患者心力衰竭风险增加有关。线粒体功能障碍被认为是糖尿病心肌病的潜在因素。心肌线粒体具有亚细胞空间位置的特征，包括位于肌膜下的线粒体、肌膜下线粒体(SSM)和位于肌原纤维之间的线粒体、纤维间线粒体(IFM)。这项研究的目的是确定1型糖尿病心脏损害是否影响空间上不同线粒体亚群的蛋白质组组成，并评估核编码线粒体蛋白输入的作用。利用多种蛋白质组学方法(iTRAQ和双向差示凝胶内电泳法)，1型糖尿病对IFM蛋白质组组成的影响比SSM更大，表现为脂肪酸氧化和电子传递链蛋白质的丰度降低。糖尿病IFM患者线粒体磷酸载体和腺嘌呤核苷酸转运体以及内膜转位酶均减少(P<；0.05)。米托菲林是一种与眉骨形态有关的蛋白质，在糖尿病IFM中减少(P<；0.05)。翻译后修饰，包括氧化和脱酰胺，在糖尿病IFM中最为普遍。糖尿病IFM患者线粒体热休克蛋白70(MtHsp70)表达显著降低(P<；0.05)。糖尿病IFM组线粒体蛋白输入减少，而糖尿病SSM组无明显变化(P<；0.05)。综上所述，这些结果表明，1型糖尿病心脏线粒体蛋白质组的改变在IFM中更为明显。此外，蛋白质组的改变与核编码的线粒体蛋白导入功能障碍和重要的线粒体蛋白导入成分mtHsp70的丢失有关，这一过程与糖尿病心脏的发病机制有关。
Baseler WA, Dabkowski ER, Williamson CL, Croston TL, Thapa D, Powell MJ, Razunguzwa TT, Hollander JM. Proteomic alterations of distinct mitochondrial subpopulations in the type 1 diabetic heart: contribution of protein import dysfunction. Am J Physiol Regul Integr Comp Physiol 300: R186-R200, 2011. First published November 3, 2010; doi: 10.1152/ajpregu.00423.2010.-Diabetic cardiomyopathy is associated with increased risk of heart failure in type 1 diabetic patients. Mitochondrial dysfunction is suggested as an underlying contributor to diabetic cardiomyopathy. Cardiac mitochondria are characterized by subcellular spatial locale, including mitochondria located beneath the sarcolemma, subsarcolemmal mitochondria (SSM), and mitochondria situated between the myofibrils, interfibrillar mitochondria (IFM). The goal of this study was to determine whether type 1 diabetic insult in the heart influences proteomic make-up of spatially distinct mitochondrial subpopulations and to evaluate the role of nuclear encoded mitochondrial protein import. Utilizing multiple proteomic approaches (iTRAQ and two-dimensional-differential in-gel electrophoresis), IFM proteomic make-up was impacted by type 1 diabetes mellitus to a greater extent than SSM, as evidenced by decreased abundance of fatty acid oxidation and electron transport chain proteins. Mitochondrial phosphate carrier and adenine nucleotide translocator, as well as inner membrane translocases, were decreased in the diabetic IFM (P < 0.05 for both). Mitofilin, a protein involved in cristae morphology, was diminished in the diabetic IFM (P < 0.05). Posttranslational modifications, including oxidations and deamidations, were most prevalent in the diabetic IFM. Mitochondrial heat shock protein 70 (mtHsp70) was significantly decreased in diabetic IFM (P < 0.05). Mitochondrial protein import was decreased in the diabetic IFM with no change in the diabetic SSM (P < 0.05). Taken together, these results indicate that mitochondrial proteomic alterations in the type 1 diabetic heart are more pronounced in the IFM. Further, proteomic alterations are associated with nuclear encoded mitochondrial protein import dysfunction and loss of an essential mitochondrial protein import constituent, mtHsp70, implicating this process in the pathogenesis of the diabetic heart.